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1.
Respir Res ; 20(1): 65, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940135

RESUMO

BACKGROUND: Multiple gene expression studies have been performed separately in peripheral blood, lung, and airway tissues to study COPD. We performed RNA-sequencing gene expression profiling of large-airway epithelium, alveolar macrophage and peripheral blood samples from the same subset of COPD cases and controls from the COPDGene study who underwent bronchoscopy at a single center. Using statistical and gene set enrichment approaches, we sought to improve the understanding of COPD by studying gene sets and pathways across these tissues, beyond the individual genomic determinants. METHODS: We performed differential expression analysis using RNA-seq data obtained from 63 samples from 21 COPD cases and controls (includes four non-smokers) via the R package DESeq2. We tested associations between gene expression and variables related to lung function, smoking history, and CT scan measures of emphysema and airway disease. We examined the correlation of differential gene expression across the tissues and phenotypes, hypothesizing that this would reveal preserved and private gene expression signatures. We performed gene set enrichment analyses using curated databases and findings from prior COPD studies to provide biological and disease relevance. RESULTS: The known smoking-related genes CYP1B1 and AHRR were among the top differential expression results for smoking status in the large-airway epithelium data. We observed a significant overlap of genes primarily across large-airway and macrophage results for smoking and airway disease phenotypes. We did not observe specific genes differentially expressed in all three tissues for any of the phenotypes. However, we did observe hemostasis and immune signaling pathways in the overlaps across all three tissues for emphysema, and amyloid and telomere-related pathways for smoking. In peripheral blood, the emphysema results were enriched for B cell related genes previously identified in lung tissue studies. CONCLUSIONS: Our integrative analyses across COPD-relevant tissues and prior studies revealed shared and tissue-specific disease biology. These replicated and novel findings in the airway and peripheral blood have highlighted candidate genes and pathways for COPD pathogenesis.


Assuntos
Perfilação da Expressão Gênica/métodos , Macrófagos Alveolares/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Mucosa Respiratória/metabolismo , Análise de Sequência de RNA/métodos , Estudos de Coortes , Seguimentos , Humanos , Estudos Longitudinais , Macrófagos Alveolares/patologia , Doença Pulmonar Obstrutiva Crônica/patologia , Mucosa Respiratória/patologia
2.
Nat Genet ; 51(3): 494-505, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804561

RESUMO

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.


Assuntos
Predisposição Genética para Doença/genética , Doença Pulmonar Obstrutiva Crônica/genética , Adulto , Idoso , Asma/genética , Estudos de Casos e Controles , Feminino , Expressão Gênica/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fibrose Pulmonar/genética , Fumar/genética
3.
Respir Res ; 20(1): 5, 2019 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-30621695

RESUMO

BACKGROUND: Previous studies have identified lung, sputum or blood transcriptomic biomarkers associated with the severity of airflow limitation in COPD. Yet, it is not clear whether the lung pathobiology is mirrored by these surrogate tissues. The aim of this study was to explore this question. METHODS: We used Weighted Gene Co-expression Network Analysis (WGCNA) to identify shared pathological mechanisms across four COPD gene-expression datasets: two sets of lung tissues (L1 n = 70; L2 n = 124), and one each of induced sputum (S; n = 121) and peripheral blood (B; n = 121). RESULTS: WGCNA analysis identified twenty-one gene co-expression modules in L1. A robust module preservation between the two L datasets was observed (86%), with less preservation in S (33%) and even less in B (23%). Three modules preserved across lung tissues and sputum (not blood) were associated with the severity of airflow limitation. Ontology enrichment analysis showed that these modules included genes related to mitochondrial function, ion-homeostasis, T cells and RNA processing. These findings were largely reproduced using the consensus WGCNA network approach. CONCLUSIONS: These observations indicate that major differences in lung tissue transcriptomics in patients with COPD are poorly mirrored in sputum and are unrelated to those determined in blood, suggesting that the systemic component in COPD is independently regulated. Finally, the fact that one of the preserved modules associated with FEV1 was enriched in mitochondria-related genes supports a role for mitochondrial dysfunction in the pathobiology of COPD.


Assuntos
Volume Expiratório Forçado/fisiologia , Redes Reguladoras de Genes/genética , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/genética , Escarro/metabolismo , Transcriptoma/genética , Idoso , Estudos de Coortes , Bases de Dados Genéticas/tendências , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/metabolismo , Escarro/química
4.
Respir Res ; 19(1): 46, 2018 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-29566699

RESUMO

BACKGROUND: Genome-wide association studies have identified several genetic risk loci for severe chronic obstructive pulmonary disease (COPD) and emphysema. However, these studies do not fully explain disease heritability and in most cases, fail to implicate specific genes. Integrative methods that combine gene expression data with GWAS can provide more power in discovering disease-associated genes and give mechanistic insight into regulated genes. METHODS: We applied a recently described method that imputes gene expression using reference transcriptome data to genome-wide association studies for two phenotypes (severe COPD and quantitative emphysema) and blood and lung tissue gene expression datasets. We further tested the potential causality of individual genes using multi-variant colocalization. RESULTS: We identified seven genes significantly associated with severe COPD, and five genes significantly associated with quantitative emphysema in whole blood or lung. We validated results in independent transcriptome databases and confirmed colocalization signals for PSMA4, EGLN2, WNT3, DCBLD1, and LILRA3. Three of these genes were not located within previously reported GWAS loci for either phenotype. We also identified genetically driven pathways, including those related to immune regulation. CONCLUSIONS: An integrative analysis of GWAS and gene expression identified novel associations with severe COPD and quantitative emphysema, and also suggested disease-associated genes in known COPD susceptibility loci. TRIAL REGISTRATION: NCT00608764 , Registry: ClinicalTrials.gov, Date of Enrollment of First Participant: November 2007, Date Registered: January 28, 2008 (retrospectively registered); NCT00292552 , Registry: ClinicalTrials.gov, Date of Enrollment of First Participant: December 2005, Date Registered: February 14, 2006 (retrospectively registered).


Assuntos
Estudo de Associação Genômica Ampla/métodos , Genômica/métodos , Doença Pulmonar Obstrutiva Crônica/genética , Enfisema Pulmonar/genética , Índice de Gravidade de Doença , Ensaios Clínicos como Assunto/métodos , Estudos de Coortes , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/epidemiologia
5.
Am J Respir Crit Care Med ; 197(10): 1275-1284, 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29313708

RESUMO

RATIONALE: As the third leading cause of death in the United States, the impact of chronic obstructive pulmonary disease (COPD) makes identification of its molecular mechanisms of great importance. Genome-wide association studies (GWASs) have identified multiple genomic regions associated with COPD. However, genetic variation only explains a small fraction of the susceptibility to COPD, and sub-genome-wide significant loci may play a role in pathogenesis. OBJECTIVES: Regulatory annotation with epigenetic evidence may give priority for further investigation, particularly for GWAS associations in noncoding regions. We performed integrative genomics analyses using DNA methylation profiling and genome-wide SNP genotyping from lung tissue samples from 90 subjects with COPD and 36 control subjects. METHODS: We performed methylation quantitative trait loci (mQTL) analyses, testing for SNPs associated with percent DNA methylation and assessed the colocalization of these results with previous COPD GWAS findings using Bayesian methods in the R package coloc to highlight potential regulatory features of the loci. MEASUREMENTS AND MAIN RESULTS: We identified 942,068 unique SNPs and 33,996 unique CpG sites among the significant (5% false discovery rate) cis-mQTL results. The genome-wide significant and subthreshold (P < 10-4) GWAS SNPs were enriched in the significant mQTL SNPs (hypergeometric test P < 0.00001). We observed enrichment for sites located in CpG shores and shelves, but not CpG islands. Using Bayesian colocalization, we identified loci in regions near KCNK3, EEFSEC, PIK3CD, DCDC2C, TCERG1L, FRMD4B, and IL27. CONCLUSIONS: Colocalization of mQTL and GWAS loci provides regulatory characterization of significant and subthreshold GWAS findings, supporting a role for genetic control of methylation in COPD pathogenesis.

6.
Hum Genomics ; 12(1): 1, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29335020

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) significantly associated with chronic obstructive pulmonary disease (COPD). However, many genetic variants show suggestive evidence for association but do not meet the strict threshold for genome-wide significance. Integrative analysis of multiple omics datasets has the potential to identify novel genes involved in disease pathogenesis by leveraging these variants in a functional, regulatory context. RESULTS: We performed expression quantitative trait locus (eQTL) analysis using genome-wide SNP genotyping and gene expression profiling of lung tissue samples from 86 COPD cases and 31 controls, testing for SNPs associated with gene expression levels. These results were integrated with a prior COPD GWAS using an ensemble statistical and network methods approach to identify relevant genes and observe them in the context of overall genetic control of gene expression to highlight co-regulated genes and disease pathways. We identified 250,312 unique SNPs and 4997 genes in the cis(local)-eQTL analysis (5% false discovery rate). The top gene from the integrative analysis was MAPT, a gene recently identified in an independent GWAS of lung function. The genes HNRNPAB and PCBP2 with RNA binding activity and the gene ACVR1B were identified in network communities with validated disease relevance. CONCLUSIONS: The integration of lung tissue gene expression with genome-wide SNP genotyping and subsequent intersection with prior GWAS and omics studies highlighted candidate genes within COPD loci and in communities harboring known COPD genes. This integration also identified novel disease genes in sub-threshold regions that would otherwise have been missed through GWAS.

7.
PLoS One ; 12(10): e0185682, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29016655

RESUMO

Chronic obstructive pulmonary disease (COPD) occurs typically in current or former smokers, but only a minority of people with smoking history develops the disease. Besides environmental factors, genetics is an important risk factor for COPD. However, the relationship between genetics, environment and phenotypes is not well understood. Sample sizes for genome-wide expression studies based on lung tissue have been small due to the invasive nature of sample collection. Increasing evidence for the systemic nature of the disease makes blood a good alternative source to study the disease, but there have also been few large-scale blood genomic studies in COPD. Due to the complexity and heterogeneity of COPD, examining groups of interacting genes may have more relevance than identifying individual genes. Therefore, we used Weighted Gene Co-expression Network Analysis to find groups of genes (modules) that are highly connected. However, module definitions may vary between individual data sets. To alleviate this problem, we used a consensus module definition based on two cohorts, COPDGene and ECLIPSE. We studied the relationship between the consensus modules and COPD phenotypes airflow obstruction and emphysema. We also used these consensus module definitions on an independent cohort (TESRA) and performed a meta analysis involving all data sets. We found several modules that are associated with COPD phenotypes, are enriched in functional categories and are overrepresented for cell-type specific genes. Of the 14 consensus modules, three were strongly associated with airflow obstruction (meta p ≤ 0.0002), and two had some association with emphysema (meta p ≤ 0.06); some associations were stronger in the case-control cohorts, and others in the cases-only subcohorts. Gene Ontology terms that were overrepresented included "immune response" and "defense response." The cell types whose type-specific genes were overrepresented in modules (p < 0.05) included natural killer cells, dendritic cells, and neutrophils. Together, this is the largest investigation of gene blood expression in COPD with 469 cases in COPDGene, ECLIPSE and TESRA combined, with 6267 genes common to all data sets. Additional, we have 42 and 83 controls in COPDGene and ECLIPSE, respectively.


Assuntos
Interação Gene-Ambiente , Genômica , Doença Pulmonar Obstrutiva Crônica/sangue , Enfisema Pulmonar/sangue , Epistasia Genética , Expressão Gênica/genética , Ontologia Genética , Humanos , Monócitos/metabolismo , Monócitos/patologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Enfisema Pulmonar/genética , Fatores de Risco , Espirometria
8.
Chronic Obstr Pulm Dis ; 4(2): 97-108, 2017 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-28848918

RESUMO

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder. COPD patients may have different clinical features, imaging characteristics and natural history. Multiple studies have investigated heterogeneity using statistical methods such as unsupervised clustering to define different subgroups of COPD based largely on clinical phenotypes. Some studies have performed clustering using genetic data or limited numbers of blood biomarkers. Our primary goal was to use proteomic data to find subtypes of COPD within clinically similar individuals. In the Treatment of Emphysema with a gamma-Selective Retinoid Agonist (TESRA) study, multiplex biomarker panels were run in serum samples collected prior to randomization. After implementing an algorithm to minimize missing values, the dataset included 396 COPD individuals and 87 biomarkers. Using hierarchical clustering, we identified 3 COPD subgroups, containing 267 (67.4%), 104 (26.3%), and 25 (6.3%) individuals, respectively. The third cluster had less emphysema on quantitative analysis of chest computed tomography scans (p=0.03) and worse disease-related quality of life based on the St. George's Respiratory Questionnaire (total score cluster 1: 45.6, cluster 2: 45.4, cluster 3: 56.6; p=0.01), despite similar levels of lung function impairment (forced expiratory volume in 1 second (49.2%, 49.2%, 48.2 % predicted, respectively). Enrichment analysis showed the biomarkers distinguishing cluster 3 mapped to platelet alpha granule and cell chemotaxis pathways. Thus, we identified a subgroup which has less emphysema but may have greater inflammation, which could be potentially targeted with anti-inflammatory therapies.

9.
Sci Rep ; 7: 44232, 2017 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-28287180

RESUMO

In comparison to genome-wide association studies (GWAS), there has been poor replication of gene expression studies in chronic obstructive pulmonary disease (COPD). We performed microarray gene expression profiling on a large sample of resected lung tissues from subjects with severe COPD. Comparing 111 COPD cases and 40 control smokers, 204 genes were differentially expressed; none were at significant GWAS loci. The top differentially expressed gene was HMGB1, which interacts with AGER, a known COPD GWAS gene. Differentially expressed genes showed enrichment for putative interactors of the first three identified COPD GWAS genes IREB2, HHIP, and FAM13A, based on gene sets derived from protein and RNA binding studies, RNA-interference, a murine smoking model, and expression quantitative trait locus analyses. The gene module most highly associated for COPD in Weighted Gene Co-Expression Network Analysis (WGCNA) was enriched for B cell pathways, and shared seventeen genes with a mouse smoking model and twenty genes with previous emphysema studies. As in other common diseases, genes at COPD GWAS loci were not differentially expressed; however, using a combination of network methods, experimental studies and careful phenotype definition, we found differential expression of putative interactors of these genes, and we replicated previous human and mouse microarray results.


Assuntos
Regulação da Expressão Gênica , Loci Gênicos , Estudo de Associação Genômica Ampla , Pulmão/metabolismo , Doença Pulmonar Obstrutiva Crônica , Adulto , Idoso , Animais , Feminino , Humanos , Pulmão/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Índice de Gravidade de Doença
10.
Am J Respir Cell Mol Biol ; 56(3): 332-341, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27854507

RESUMO

Chronic obstructive pulmonary disease (COPD) is a complex disease with strong environmental and genetic influences and sexually dimorphic features. Although genetic risk factors for COPD have been identified, much of the heritability remains unexplained. Sex-based genetic association studies may uncover additional COPD genetic risk factors. We studied current and former smokers from COPD case-control cohorts (COPDGene non-Hispanic whites and African Americans, Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points, and Genetics of Chronic Obstructive Lung Disease). COPD was defined as post-bronchodilator forced expiratory volume in 1 second/forced vital capacity less than 0.70 and forced expiratory volume in 1 second percent predicted less than 80. Testing was performed across all cohorts and combined in a meta-analysis adjusted for age, pack-years, and genetic ancestry. We first performed genome-wide single-nucleotide polymorphism (SNP)-by-sex interaction testing on the outcome of COPD affection status. We performed sex-stratified association testing for SNPs with interaction P less than 10-6. We examined over 8 million SNPs in four populations, including 6,260 subjects with COPD (40.6% female) and 5,269 smoking control subjects (47.3% female). The SNP rs9615358 in the cadherin gene CELSR1 approached genome-wide significance for an interaction with sex (P = 1.24 × 10-7). In the sex-stratified meta-analysis, this SNP was associated with COPD among females (odds ratio, 1.37 [95% confidence interval, 1.25-1.49]; P = 3.32 × 10-7) but not males (odds ratio, 0.90 [95% confidence interval, 0.79-1.01]; P = 0.06). CELSR1 is involved in fetal lung development. In a human fetal lung tissue dataset, we observed greater CELSR1 expression in female compared with male samples. This SNP-by-sex genome-wide association analysis identified the fetal lung development gene, CELSR1, as a potential sex-specific risk factor for COPD. Identifying sex-specific genetic risk factors may reveal new insights into sexually dimorphic features of COPD.


Assuntos
Caderinas/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Doença Pulmonar Obstrutiva Crônica/genética , Idoso , Alelos , Demografia , Feminino , Regulação da Expressão Gênica , Humanos , Pulmão/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
11.
Epigenetics ; : 1-10, 2016 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-27564456

RESUMO

Chronic obstructive pulmonary disease (COPD) is a smoking-related disease characterized by genetic and phenotypic heterogeneity. Although association studies have identified multiple genomic regions with replicated associations to COPD, genetic variation only partially explains the susceptibility to lung disease, and suggests the relevance of epigenetic investigations. We performed genome-wide DNA methylation profiling in homogenized lung tissue samples from 46 control subjects with normal lung function and 114 subjects with COPD, all former smokers. The differentially methylated loci were integrated with previous genome-wide association study results. The top 535 differentially methylated sites, filtered for a minimum mean methylation difference of 5% between cases and controls, were enriched for CpG shelves and shores. Pathway analysis revealed enrichment for transcription factors. The top differentially methylated sites from the intersection with previous GWAS were in CHRM1, GLT1D1, and C10orf11; sorted by GWAS P-value, the top sites included FRMD4A, THSD4, and C10orf11. Epigenetic association studies complement genetic association studies to identify genes potentially involved in COPD pathogenesis. Enrichment for genes implicated in asthma and lung function and for transcription factors suggests the potential pathogenic relevance of genes identified through differential methylation and the intersection with a broader range of GWAS associations.

12.
BMC Med Genomics ; 8: 1, 2015 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-25582225

RESUMO

BACKGROUND: Exacerbations of chronic obstructive pulmonary disease (COPD), characterized by acute deterioration in symptoms, may be due to bacterial or viral infections, environmental exposures, or unknown factors. Exacerbation frequency may be a stable trait in COPD patients, which could imply genetic susceptibility. Observing the genes, networks, and pathways that are up- and down-regulated in COPD patients with differing susceptibility to exacerbations will help to elucidate the molecular signature and pathogenesis of COPD exacerbations. METHODS: Gene expression array and plasma biomarker data were obtained using whole-blood samples from subjects enrolled in the Treatment of Emphysema With a Gamma-Selective Retinoid Agonist (TESRA) study. Linear regression, weighted gene co-expression network analysis (WGCNA), and pathway analysis were used to identify signatures and network sub-modules associated with the number of exacerbations within the previous year; other COPD-related phenotypes were also investigated. RESULTS: Individual genes were not found to be significantly associated with the number of exacerbations. However using network methods, a statistically significant gene module was identified, along with other modules showing moderate association. A diverse signature was observed across these modules using pathway analysis, marked by differences in B cell and NK cell activity, as well as cellular markers of viral infection. Within two modules, gene set enrichment analysis recapitulated the molecular signatures of two gene expression experiments; one involving sputum from asthma exacerbations and another involving viral lung infections. The plasma biomarker myeloperoxidase (MPO) was associated with the number of recent exacerbations. CONCLUSION: A distinct signature of COPD exacerbations may be observed in peripheral blood months following the acute illness. While not predictive in this cross-sectional analysis, these results will be useful in uncovering the molecular pathogenesis of COPD exacerbations.


Assuntos
Biologia Computacional/métodos , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Doença Pulmonar Obstrutiva Crônica/genética , Idoso , Algoritmos , Biomarcadores/sangue , Estudos Transversais , Enfisema/sangue , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Fenótipo , Doença Pulmonar Obstrutiva Crônica/sangue , Análise de Sequência de RNA , Índice de Gravidade de Doença , Transcriptoma
13.
Genome Biol Evol ; 4(12): 1256-62, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23160175

RESUMO

It has become clear that different genome regions need not evolve uniformly. This variation is particularly evident in bacterial genomes with multiple chromosomes, in which smaller, secondary chromosomes evolve more rapidly. We previously demonstrated that substitution rates and gene dispensability were greater on secondary chromosomes in many bacterial genomes. In Vibrio, the secondary chromosome is replicated later during the cell cycle, which reduces the effective dosage of these genes and hence their expression. More rapid evolution of secondary chromosomes may therefore reflect weaker purifying selection on less expressed genes. Here, we test this hypothesis by relating substitution rates of orthologs shared by multiple Burkholderia genomes, each with three chromosomes, to a study of gene expression in genomes differing by a major reciprocal translocation. This model predicts that expression should be greatest on chromosome 1 (the largest) and least on chromosome 3 (the smallest) and that expression should tend to decline within chromosomes from replication origin to terminus. Moreover, gene movement to the primary chromosome should associate with increased expression, and movement to secondary chromosomes should result in reduced expression. Our analysis supports each of these predictions, as translocated genes tended to shift expression toward their new chromosome neighbors despite inevitable cis-acting regulation of expression. This study sheds light on the early dynamics of genomes following rearrangement and illustrates how secondary chromosomes in bacteria may become evolutionary test beds.


Assuntos
Burkholderia/genética , Evolução Molecular , Genes Bacterianos , Translocação Genética , Cromossomos Bacterianos/genética , Expressão Gênica , Genoma Bacteriano
14.
ISRN Bioinform ; 2012: 371718, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-25937939

RESUMO

Accurate base calls generated from sequencing data are required for downstream biological interpretation, particularly in the case of rare variants. CallSim is a software application that provides evidence for the validity of base calls believed to be sequencing errors and it is applicable to Ion Torrent and 454 data. The algorithm processes a single read using a Monte Carlo approach to sequencing simulation, not dependent upon information from any other read in the data set. Three examples from general read correction, as well as from error-or-variant classification, demonstrate its effectiveness for a robust low-volume read processing base corrector. Specifically, correction of errors in Ion Torrent reads from a study involving mutations in multidrug resistant Staphylococcus aureus illustrates an ability to classify an erroneous homopolymer call. In addition, support for a rare variant in 454 data for a mixed viral population demonstrates "base rescue" capabilities. CallSim provides evidence regarding the validity of base calls in sequences produced by 454 or Ion Torrent systems and is intended for hands-on downstream processing analysis. These downstream efforts, although time consuming, are necessary steps for accurate identification of rare variants.

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